Basic amides of 3-thianaphthene carboxylic acid



United States Patent 2,876,235.? 1 BASIC AMIDES or 3-THIANAPHTl-lENE-j1.

cAR oXymo-Acm. a

Walter VoegtliyBase];"Switzerland, .:assignor-.to G.

Searle & 'Co., Chicago, 111., a corporationof Delaware No Drawing.ApplicationDece'mber 3, 1956 Serial No. 625,611

4 Claims. or. 260-3305)? Thepresent invention is concerned'with basicamides-" of 3-thianaphthenecarboxylic acid and with non-toxic saltsthereof. More particularly, it is concerned with compositions which, inthe forms of their-:frem-bases, can be represented by the'structuralformula:

CONE-,Z.

In this formula theterm Z can represe t a lower dialkyl-haminoalkyl'radical or a pyridyl radical. 'By the'e'xpr'e'si sion lowerdialkylamin'oalkyl there is meant an organic.- radical of the structuralformula can consequently represent suchipolymethylene radicals asethylene, trimethylene, ,tetramethylene, penta'methylone, hexamethylene,heptamethylene and ,octamethylene,- as wellas isomericpropylene,butylene, amyleneihexyle ene, heptylene, andoctylenelradicals'. ,Pyridylfradicals encompassed by the terrnZinclude.;2.-pyridyl, 3.-pyridyl. andfkpyridyl. a

In the manufactureofcompositions of this invention,;3-thianaphthenecarboxylic acid of the structuralforinula.

is converted to the acid chloride, which is then reacted, suitably in anethereal or hydrocarbon medium, with a diamine such as adialkylaminoalkylarnine or an amino.

pyridine.,. .The amide'which. is the-reaction productcan".

be obtained directly aslits' hydrochloride, or after basifica:

tion with a reagent such as potassium carbonate or-s'o-f diumhydroxide,.as the free base.

The free bases of this invention can sometimes. be

obtained as crystallizable solids and sometimes {as highboiling oilswhich can be subjected to purification by. dlSr tillation in ashort-path distillation apparatus at pressures of approximately.0.02mmqi Theorganicbases of this inventionforrn acid-addition:-

and quaternary ammonium salts, non-toxic except-gashereinafterdisclosed, with a \varietysof organic and inora ganicsalt-forming reagents. Thus, acid-addition salts}, formed by admixtureof the organic free base with an acid, suitably in a neutral solvent,are formed with such acids as sulfuric, phosphoric, hydrochloric,hydrobromic, hydriodic, sulfamic, citric, lactic, maleic, malic,

succinic, tartaric, cinnamic, acetic, benzoic, gluconic, ascorbic, andrelated acids. Quaternary ammonium salts can be formed by reaction ofthe free bases with a variety of organic esters of sulfuric hydrohalic,and aromatic sulfonic acids.: Theorganic esters employed for quaternaryammonium salt formation are desirablylower alkyl halides, and alkylenehalohydrins such as ethylene bromohydrin. However, other organic estersare suitable for salt formatiom'a'nd'canibe selected from among adiverse class'of compoundsincludingbenzylchloride, phenethyl chloride,naphthylrnethyl chloride, dimethyl sulfate;

methyl benz'enesulfonate, ethyl toluenesulfonate', allyl chloride,methallyl bromide and crotyl bromide." For the purposes of thisinvention the free bases are equivalent 'to their non toxioacid-addition and quarternary' ammonium" salts;

The. compositions of this invention have valuable phar--- macologicalproperties, as shown "by their'eiiects on'the cardiovascular system.They are anti-hypertensive agents, and are effective in reducingelevated blood pressure.

They'are also effective in the treatment of cardiac arrhythmias, and,like quinidine, can be employed in normaliz ing atrial flutterand'atrial fibrillation. One of the advantages of the compositionsclaimed herein is that they are relatively non-toxic to higher forms oflife; they do,

however, display toxicity toward lower forms of'life, and can.consequently be employed as anti-fungal. agents.- Thus, they areeffective by topical application in inhibit-1 ing the growth of Trichophyton 'mentagrophytes.

This invention will appearmore fully from the examplesj which follow.These examples are set forth by way of illustration only, and it will beunderstood that the invention is not to be construed as limited inspirit 7 or in scope by the details contained therein, as manymodifications in materials and methods will be apparent a from thisdisclosure tothose skilled in the art. In these examplestemperatures-are given in degrees centigrade" C.), distillationpressures in millimeters (mm.) of

'mercury, and quantities of materials in parts by weight.

Example 1 A solution of 4 parts of 3-thianaphthenecarhoxylic acid in 65parts of thionyl chloride is allowed to stand at about 25 C. for 18hours and is then heated under reflux for 2 hours.

each are added to the residue and likewise removed by vacuumdistillation. The non-volatile ,resi-due' readily crystallizes, and isS-thianaphtheneCarbonyl chloride which is suitable for use withoutfurther purification. The structural formula is Example 2 To a stirredsolution of 6.6 parts of 3-thianaphthenecarbonyl chloride in parts ofanhydrousether, cooled with an external ice bath, there is added asolution of 4.3 parts of 3-diethylaminopropylamine in 110 parts of an-The hydrous ether over a period of about 30 minutes. reaction'mixture isstirred at room temperature for an additional3 hours, and .then'allowedto stand for about 20 hours.- The" insoluble product is thencollectedon a filter and washed with ether. '.An aqueous solutionofthis'L' product is rendered basic with saturated potassium carbonatesolution and extracted with several portions of chloroform. The combinedchloroform extract is washed with water, and concentrated to dryness bydistillation of the solvent under reduced pressure, finally at atemperature of about C. at a pressure of about Patented Mar. 3, 1959The'thionyl chloride is removed by distillation under reduced pressure,following which at least two separate portions of anhydrous benzene ofabout 1 0 parts 20 mm. The viscous, red oil which remains is crude N-(3-diethylaminopropyl)3-thianaphthenecarboxamide. In a short-pathdistillation apparatus it is obtained as a yellowoil which boils atabout l75-180 C. at 0.02 mm. The structural formula is 5 By theforegoingprocedure, with the substitution of 3.4 parts. of3-dimethylaminopropylamine for the 3-diethyl aminopropylamine, thecompound obtained is N-(3-dimethylaminopropyl-3-thianaphthenecarboxamide.

A methobromide is obtained from each of the foregoingdialkylaminoalkylamides by treating a chloroform solution of 1.8 partsof: the free base with 0.6 part of methyl bromide, heating the reactionmixture in a sealed vessel at about 70 C. for hours, and removing thechloroform by vaporization.

Example 3 A solution ofN-(3-diethylaminopropyl)-3-thianaphthenecarboxamide in acetone istreated with a slight .excess of hydrogen chloride in isopropyl alcohol,and crystallization is induced. The solid product is collected on afilter and washed with acetone and then with ether. This compound is N(3-diethylaminopropyl) 3-thianaphthene- -carboxamide hydrochloride whichmelts at about Example 4 To a stirred solution of 4.4 parts of3-thianaphthenecarbonyl chloride in 70 parts of anhydrous ether, keptcool with an external ice bath, there is added'a solution of 3.5 partsof S-diethylamino-Z-pentylamine in 70 parts of anhydrous ether over aperiod of about 30 minutes. The mixture is stirred at about C. for anadditional 4 hours, after which the reaction product is dis- This freebase affords a water-soluble salt by treatment with aqueous citric acid.

Example 5 To a stirred solution of 4.4 parts of 3-thianaphthenecarbonylchloride in 70 parts of anhydrous ether, kept cool with an external icebath, there is added a solution of 2.2'parts of S-aminopyridine in 70parts of anhydrous ether over a period of about minutes. A yellow,insoluble product begins to separate almost immediately. The mixture isstirred at about 25 C. for an additional 2 hours; 100 parts of water isadded, and the ether is removed 'by decantation and discarded. There isthen added 40 parts of methanol and 200 parts of water, and, withvigorous stirring, the mixture is made basic with saturated potassiumcarbonate solution. This operation causes the formation of an oilyproduct, which quickly tends to harden. This oily or.s0lidified productis dissolved by extraction with several-portions of chloroform, and thecombined chloroform extract is washed with water, dried over potassiumcarbonate, filtered and distilled to dryness. The residue obtained is ayellow oil which readily crystallizes. Upon recrystallization fromaqueous isopropyl alcohol, there is obtained N-(3-pyridyl)-3-thianaphthenecarboxamide which melts at about 139-140 C. andhas the structural formula CONH N By the foregoing procedure, with thesubstitution of 2.2 parts of 4-aminopyridine for the 3-aminopyridine,the

compound obtained is N-(4-pyridyl)-3-thianaphthenecar-' boxamide.

' Example 6 A solution of 2 partsofiN-(3-pyridyl)-3-thianaphthenecarboxamide in 12 parts of ethanol istreated with a slight excess over 1 molecular equivalent of hydrogenchloride in isopropyl alcohol. A crystalline product begins to separatealmost immediately. Acetone (about 25 parts) is added, and the productis collected on a filter and washed with acetone and with ether. Thiscompound is N (3-pyridyl)-3-thianaphthenecarboxamide hydrochlo-f ridewhich melts at about. 249-252f C. after prior softening.

In the same manner the hydrobromide is obtained by treatment of anethanolic solution of the free base with approximately one molecularequivalent of hydrogen bromide in isopropyl alcohol.

Example 7 A reaction mixture prepared by adding 2 parts of methyl iodideto a solution of 1 part of N-(3-pyridyl)-3- thianaphthenecarboxamide in8 parts of acetone is allowed to stand at about 25 C. for 18 hours. Thecrystalline product is collected on a filter and washed with acetone andwith petroleum ether. It is recrystallized by suspending it in about 35parts of refluxing methanol, adding a small quantity of water to effectsubstantially complete solution, and allowing the filtered solution tocool. There is in this manner obtainedN-(3-pyridyl)-3-thianaphtheriecarboxamide methiodide which melts atabout 253,- 255 C.

What is claimed is:

1. A compound of the structural formula C ONHAN (lower alkyl);

wherein -A is a lower alkylene radical separating the groups attachedthereto by at least two carbon atoms.

2. N (3 diethylaminopropyl) 3 thianaphthenecarboxarnide.

3. N (3 dimethylaminopropyl) 3 thianaphthene-v carboxamide.

4. N (5 diethylamino 2 pentyl) 3 thianaph-t.

thenecarboxamide.

References Cited inthe file of this patent Wegler et al.: Chem.Abstracts, vol. "32, column 939 (1938).

Shirley et al.: 9958-9 (1953).

Chem. Abstracts, vol. 47, columns;

1. A COMPOUND OF THE STRUCTURAL FORMULA